In spite of advances in treatment options for patients with head and neck cancer the survival rates have not changed appreciably in nearly thirty years. A subset of patients at each stage of disease fails to respond regardless of the therapy they receive. The fraction of patients whose tumors relapse quickly and cause death is significant even at Stage I and increases significantly with each higher stage. Thus, although 90 percent of stage I patients can be cured either by surgery or radiation therapy, 10 percent relapse and die. For patients at Stage II, the fraction of aggressive tumors rises to 30%, to 50% at Stage III and to >70% at Stage IV. Thus, the early identification of most aggressive neoplasms is an important goal so that suitably aggressive therapy can be employed for this most lethal group of tumors. It is likely that survival will be prolonged and some of these patients will be cured when disseminated disease is microscopic. Furthermore, the identification of mechanisms of aggressive tumor behavior will also provide new targets for therapy. We postulate that specific genetic changes determine the biological behavior of individual tumors and we have focused our research on genetic markers associated with aggressive tumor behavior and response to therapy. We previously reported that loss of chromosome 18q develops with tumor progression and is associated with significantly decreased survival in head and neck cancer patients. Recently we discovered that tumors with loss of chromosome 18q23 also have loss of expression of galanin receptor 1 (GALR1), which maps to 18q23, and this is accompanied by gain of expression of another receptor, galanin receptor 2 (GALR2). GALR1 and GALR2 are G-protein coupled receptors that signal by different G-protein pathways. GALR2 is a growth factor in small cell lung cancer. Our preliminary results show that galanin, the neuropeptide ligand that binds to these receptors, and GALR1 are expressed in normal keratinocytes, but GALR2 is not. Furthermore, anti-galanin antibody causes growth inhibition of galanin secreting tumor cells. Thus, we postulate that altered expression and function of galanin receptors identify an aggressive subset of head and neck tumors and will provide a novel target for intervention. We will extend our laboratory findings to patients' tumors to test the value of the GALRs as markers to detect aggressive neoplasms and to determine if GALR alterations predict response to therapy. We will also investigate the mechanisms of galanin signaling in HNSCC. This research should lead to identification of aggressive subsets of head and neck tumors and may result in the development of new adjuvant treatment strategies for the most lethal subset of head and neck cancers.